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Journal of Cosmetic and Laser Therapy, 2013; 15: 107113

REVIEWS OF TREATMENT STUDIES

Skin and antioxidants

BORUT POLJSAK1, RAJA DAHMANE1 & ALEKSANDAR GODIC2


1University

of Ljubljana, Faculty of Health Studies, Zdravstvena pot 5, 1000 Ljubljana,


Slovenia, and 2University of Ljubljana, Faculty of Medicine,Vrazov trg 2, 1000 Ljubljana, Slovenia
Abstract
It is estimated that total sun exposure occurs non-intentionally in three quarters of our lifetimes. Our skin is exposed to
majority of UV radiation during outdoor activities, e.g. walking, practicing sports, running, hiking, etc. and not when we
are intentionally exposed to the sun on the beach. We rarely use sunscreens during those activities, or at least not as much
and as regular as we should and are commonly prone to acute and chronic sun damage of the skin. The only protection
of our skin is endogenous (synthesis of melanin and enzymatic antioxidants) and exogenous (antioxidants, which we consume from the food, like vitamins A, C, E, etc.). UV-induced photoaging of the skin becomes clinically evident with age,
when endogenous antioxidative mechanisms and repair processes are not effective any more and actinic damage to the skin
prevails. At this point it would be reasonable to ingest additional antioxidants and/or to apply them on the skin in topical
preparations. We review endogenous and exogenous skin protection with antioxidants.
Key Words: aging, antioxidants, photoaging, skin

Introduction
More than 50.000 papers appear in Medline when a
keyword oxidative stress is typed, but not all are
related to the skin. Skin aging is a consequence of
two overlapping mechanisms, intrinsic and extrinsic
(UV-exposure, smoking) (1,2). It seems that oxidative damage is the major cause and single most
important contributor of skin aging. Not only that
the free radical production increases with age but the
ability of human skin cells to repair DNA damage
steadily reduces with years and the antioxidative
defense becomes less effective (Figure 1).
The skin contains a pool of protective antioxidants. It includes enzymatic antioxidants such as
glutathione peroxidase, superoxide dismutase and
catalase, and nonenzymatic low-molecular-weight
antioxidants such as vitamin E isoforms, vitamin C,
glutathione (GSH), uric acid, and ubiquinol (3).
Other potent antioxidants, which are in the skin, are
ascorbate, uric acid, carotenoids and sulphydrils.
Water-soluble antioxidants in plasma are glucose,
pyruvate, uric acid, ascorbic acid, bilirubin and
glutathione, and lipid-soluble are alpha-tocopherol,

ubiquinol-10, lycopene, -carotene, lutein, zeaxanthin and alpha-carotene (4). In general, surface of
the skin, the epidermis, contains higher concentrations of antioxidants than the dermis (5). Alphatocopherol is the most prominent antioxidant in the
lipophilic compartments while vitamin C and GSH
have the highest abundance in the cytosol. Hydrophilic
non-enzymatic antioxidants, including L-ascorbic
acid, GSH and uric acid are predominant antioxidants in the human skin compared on an equivalent
molar basis (6). Their overall dermal and epidermal
concentration is more than 10- to 100-fold greater
than those found for vitamin E or ubiquinol. Keratinocytes and skin fibroblasts contain milimolar levels
of GSH, -tocopherol, ascorbate, and DNA repair
enzymes. The stratum corneum (SC) was found to
contain both hydrophilic and lipophilic antioxidants.
Vitamins C and E (both and -tocopherol) as well
as GSH and uric acid were found to be present in
the SC (7,8). Surprisingly, they were not distributed
evenly, but in gradient fashion, with low concentrations in the outer layers, which increase toward the
deeper layers of the SC.

Correspondence: Aleksandar Godic, MD, PhD, Faculty of Medicine, Vrazov trg 2, 1000 Ljubljana, Slovenia. Tel: 386-51-415-678. E-mail: aleksandar.
godic@gmail.com
(Received 2 September 2012 ; accepted 3 December 2012 )
ISSN 1476-4172 print/ISSN 1476-4180 online 2013 Informa UK, Ltd.
DOI: 10.3109/14764172.2012.758380

108

B. Poljsak et al.
Cause:

Consequence:

Intrinsic free radical formation

Oxidative
stress

Skin aging

Premature skin aging


Clinical signs of the aging skin
Increased oxidative stress
Inflammatory reactions
Immunosupression
Depleated cutaneous antioxidants
Oxidised proteins, DNA and lipids
Premalignant and malignant skin lesion

Extrinsic free radical formation

Figure 1. Causes and consequences of skin aging.

Exogenous antioxidants compounds


derived from the diet
Most important preventive mechanisms against ROSinduced damage are antioxidative enzymes, non-enzymatic compounds, and repair processes, but they
are less effective with aging. It would be rational at
this point to ingest additional antioxidants or to apply
them on the skin in topical preparations. The identification of free radical reactions as promoters of the
aging process implies that interventions, which limit
their production or inhibit their interactions, reduce
the disease pathogenesis and consequently rate of
aging. Dietary antioxidants play a major role in maintaining the homeostasis of the oxidative balance. Vitamin C (ascorbic acid), vitamin E (tocopherol),
beta-carotene and other micronutrients such as carotenoids, polyphenols and selenium have been evaluated as antioxidant constituents in the human diet. It
is important to obtain many different water and lipid
soluble antioxidants by intake of different kinds of
fruits and vegetables since all antioxidants work in
synergy. Thiols, which are associated with membrane
proteins, may also be important antioxidants. Tocopherols and tocotrienols (vitamin E) and ascorbic acid
(vitamin C) as well as the carotenoids exhibit their
antioxidative properties through reacting with free
radicals, notably peroxyl radicals, and with singlet
molecular oxygen (1O2). RRR-alpha-tocopherol is
the major peroxyl radical scavenger in biological lipid
phases such as membranes or low-density lipoproteins (LDL). L-Ascorbate is present in aqueous compartments (e.g. cytosol, plasma, and other body
fluids) and can reduce the tocopheroxyl radical; it is
also important cofactor in hydroxylations. Carotenoids, notably beta-carotene and lycopene as well as
oxycarotenoids (e.g. zeaxanthin and lutein), exert
antioxidative functions in lipid phases by free-radical
or 1O2 quenching (9).
Many studies on usage of different antioxidants
or combinations of them with phytochemicals were
performed in order to find evidence against ROSinduced skin damage (10).

Recommended daily intake


The Dietary Reference Intake (DRI) is a system of
nutrition recommendations from the Institute
of Medicine (IOM) of the U.S. National Academy of
Sciences. The DRI system is used by both the United
States and Canada and is intended for the general
public and health professionals. The Reference Daily
Intake or Recommended Daily Intake (RDI) is the
daily intake level of a nutrient that is considered to
be sufficient to meet the requirements of 9798% of
healthy individuals in every demographic in the
United States (where it was developed, but has since
been adopted in other countries). The DRI values
are not currently used in nutrition labeling, where
the older Reference Daily Intakes (RDAs) are still
used. The reference values, collectively called the
Dietary Reference Intakes (DRIs), include the Recommended Dietary Allowance (RDA), the Adequate
Intake (AI), the Tolerable Upper Intake Level (UL),
and the Estimated Average Requirement (EAR). A
requirement is defined as the lowest continuing
intake level of a nutrient that, for a specified indicator of adequacy, will maintain a defined level of
nutriture in an individual (11) (Table I).
Tolerable upper intake levels (UL) were developed to caution against excessive intake of nutrients
(like vitamin A) that can be harmful in large amounts.
The exaggerated intake of antioxidant(s) could cause
antioxidative stress (12) and alter the complex system of endogenous antioxidative defense of cells or
alter the necrosis or apoptosis pathways. UL is the
highest level of consumption that is considered safe
according to current data. It is recommended that
intake of certain nutrients should be from food
source only to prevent adverse effects.
Topical application and safety risk assessment
of vitamins A, C, and E
Vitamins A, C and E are most frequently used antioxidants in skin-care products and authors of the
paper decided to present the summary of their risk

Recommended daily intake*** (**)

600 g
5 000 International Unit (IU)
Recommended Dietary Allowance*
Male: 1000 (g)a
Female: 800 (g)a

75 mg
Recommended Dietary Allowance*
Male: 60 mg
Female: 60 mg

10 mg

35 g
55 g****
50 g*****

15 mg

Nutrient

Vitamin A

Vitamin C
(ascorbic acid)

Vitamin E
(tocopherol)

Selenium

Zinc

Table I. Recommended daily intakes.

30 mg

600 g

Intakes recommended
by the FAO/WHO

40 mg

1 000 mg
Recommended Dietary
Allowance*
Male:10 (mg)b
Female: 8 (mg)b
400 g

2 000 mg

3 000 g

Tolerable upper intake


level (UL)

1150*
g/100 g

0.210

10170

Concentration in
foods (mg/100 g)
Extremely high doses
( 9 000 mg) can cause dry,
scaly skin, fatigue, nausea,
loss of appetite, bone and
joint pains and headaches.
Vitamin A is not
recommended for pregnant
women. Excess vitamin A
may cause birth defects.
However, an adequate
supply of vitamin A is still
required because of its
essential role in embryonic
development.
No impacts of over dose have
been proven so far.
Cooking may destroy vitamin
C in fruits and vegetables.
Supplements containing
bioflavonoids increase
adsorption and availability
of vitamin C. Smokers
require a larger dietary
intake of vitamin C than
non-smokers, on account of
oxidative stress in their body
caused by toxins in cigarette
smoke and generally lower
blood levels.
Doses larger than 1 000 mg
cause blood clotting, which
results in increased
likelihood of haemorrhage
in some individuals.
Doses larger than 200 g can
be toxic.
Fatigue, skin disorders,
dizziness, nausea, vomiting,
anxiety and hair loss.
Doses larger than 25 mg may
cause anaemia and copper
deficiency.

Over dosage (mg or g/d),


side-effects and warnings

(Continued)

oysters, fortified cereals,


baked beans

Brazil nuts, rockfish, yellow


fin tuna, dairy products,
potato, rice

fortified cereals, tomato


paste, sunflower seeds,
fish, meat, leafy
vegetables

Orange juice, grapefruit


juice, peaches, bell
pepper, citrus fruit.

turkey, carrot juice,


pumpkin

Significant sources

Skin and antioxidants


109

equivalents.
equivalents.

b-tocopherol

aRetinol

10 000 mg
1 250 mg
Copper

*Subcommittee on the Tenth Edition of the RDAs, Food and Nutrition Board, National Research Council (1989). Recommended Dietary Allowances, 10th Ed. National Academy Press, Washington, DC.
**Amounts for other age and gender groups, pregnant women, lactating women, and breastfeeding infants may be much different.
***Values on labels are stated Daily Reference values (DRV) of Recommended Daily Intake (RDI). The RDI is a renewed value referring to the old Recommended Dietary Allowance (RDA).
****Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes: Vitamin C, Vitamin E, Selenium, and Carotenoids. National Academy Press, Washington, DC, 2000.
*****Dietary reference intakes, Food and Nutrition Boards Institute of Medicine, National Academy Press, Washington, D.C., 19972004.

seafood (such as oysters, squid,


lobster, mussels, crab, and
clams), organ meats (such as beef
liver, kidneys, and heart), nuts
and nut butters, legumes (such as
soybeans, lentils, navy beans, and
peanuts)

Nausea, vomiting, abdominal pain,


diarrhea, metallic taste in the
mouth, fatigue, headache,
irritability, and lowered work
performance, skin pigmentation.
Abdominal pain, nausea, cramps,
diarrhea, vomiting and liver
damage.
45 mg
14 mg
Iron

Nutrient

Table 1. (Continued).

Recommended daily intake*** (**)

Intakes recommended
by the FAO/WHO

Tolerable upper intake


level (UL)

Concentration in
foods (mg/100 g)

Over dosage (mg or g/d), side-effects


and warnings

red meats, fish, chicken liver,


oysters

B. Poljsak et al.

Significant sources

110

assessment, what might be of special interest for dermatologists and other medical professionals. From the
Elmores Final report (13) of the safety assessment of
L-Ascorbic Acid, Calcium Ascorbate, Magnesium
Ascorbate, Magnesium Ascorbyl Phosphate, Sodium
Ascorbate, and Sodium Ascorbyl Phosphate as used
in cosmetics it can be concluded that they function
in cosmetic formulations primarily as antioxidants.
Ascorbic Acid is used as an antioxidant and pH
adjuster in a large variety of cosmetic formulations,
over 3/4 of which were hair dyes and colors at concentrations between 0.3 and 0.6%. For other uses, the
reported concentrations were either very low ( 0.01%)
or in the 510% range. Ascorbic Acid is generally recognized as safe (GRAS) substance for use as a chemical preservative in foods and as a nutrient and/or
dietary supplement. Ascorbic Acid was a photoprotectant in clinical human UV studies at doses well
above the minimal erythema dose (MED). One problem of vitamin C is in its instability in various topical
products, as vitamin C is prone to oxidation, and may
lose its efficacy this way. For effective topical application, vitamin C has to be non-esterified, acidic and
optimally at 20% concentration (14).
Safety and risk assessment of tocopherol and its
compounds were published in Int J Toxicol by Zondlo
in 2002. Tocopheryl Acetate, Tocopherol, and
Tocopheryl Linoleate are used in 2673 formulations,
generally at concentrations of up to 36%, 5%, and
2%, respectively, although Tocopheryl Acetate is
100% of vitamin E oil (15). Tocopherol, Tocopheryl
Acetate, Tocopheryl Linoleate, and Tocopheryl Succinate were all absorbed in human skin. Tocopherol
is a natural component of cell membranes thought
to protect against oxidative damage. Tocopherol,
Tocopheryl Acetate, and Tocopheryl Succinate each
were reported to protect against ultraviolet radiationinduced skin damage. These ingredients are generally
not toxic in animal feeding studies, although very
high doses ( 2 g/kg/day) have hemorrhagic activity.
These ingredients are generally not irritating or sensitizing to skin or irritating to eyes, although a
Tocopheryl Acetate did produce sensitization in one
animal test, and Tocophersolan was a slight eye irritant in an animal test (15). According to Burke (14),
for effective topical application, vitamin E must
be the non-esterified isomer d-alpha-tocopherol at
25% concentration. Skin penetration experiments
showed that 55% of the topically applied -tocopherol
accumulated in full thickness of the skin after 24
hours (16). Tocopherol acetate is very often used
antioxidant in sunscreen products.
Vitamin A derivatives are used as anti-aging ingredients in cosmetics. Vitamin A is absorbed through
the skin, increases the rate of epidermal keratinocytes
turnover and collagen production, and consequently
leads to more youthful appearance of the skin (17).
Topical retinoids remain the mainstay therapy of the
photoaged skin, and their efficacy can be noticed

Skin and antioxidants


clinically, evaluated histologically, and measured
biochemically. Their regular use might also prevent
photoaging (18). Available topical retinoids include
tretinoin (Retin-A), adapalene (Differen), and
tazarotene (Tazorac) and over-the-counter Retinol
and Retinol-A.These drugs are derivatives of vitamin
A which might have anti-aging properties (19).
Discussion
It is important to pretreat the skin with antioxidants
before sun exposure. Human studies have convincingly demonstrated pronounced photoprotective
effects of natural and synthetic antioxidants when
applied topically before UVR exposure. No significant
protective effect of melatonin and antioxidants (vitamins E and C), when applied either alone or in combination, were observed when antioxidants were
applied after UVR exposure even after multiple
attempts. UVR-induced skin damage starts rapidly,
and antioxidants effectively prevent such damage only
when present in relevant concentrations, at the site of
damage, and during the oxidative stress (20). Treatment of the skin with antioxidants after the UVR damage might cause additional harmful effects on cell
cycle control and apoptosis process. The photoprotective effects of antioxidants are significant when applied
in distinct mixtures and in appropriate vehicles. Usage
of topically applied creams/ointments with such combinations may improve antioxidative capacity of the
skin due to sustained antioxidative synergism. UVAinduced skin alterations are believed to be largely
determined by oxidative processes, and topical administration of antioxidants might be particularly promising (21). However, delivery of topically applied
antioxidants through the skin is hard since they must
penetrate through the epidermal barrier to reach its
site of action and they are very unstable, what makes
them difficult to formulate. Antioxidants like tocopherols, vitamin C, and flavonoids are now being added
as protective agents to the skin creams. However, their
ability to penetrate deep into the skin is limited, and
their amount in the dermis might be raised by
consuming them with the diet.
Usage of topical antioxidants is favored among
dermatologists because of their broad biologic activity. Many are not only antioxidants but also possess
anti-inflammatory and anti-carcinogenic activities,
and thus have many potential benefits. In general,
topical antioxidants exert their effects by downregulating free-radicals-mediated pathways that
damage skin (22).
Endogenous oxidative stress could be influenced
in two ways: by preventing ROS formation or by
quenching ROS with antioxidants. Results of epidemiological studies on healthy volunteers, who were
treated with oral antioxidants, are inconclusive and
even contradictory: from no effect to proven either
beneficial or harmful effect of oral antioxidant

111

supplements. None of the major clinical studies,


which used mortality or morbidity as an end point,
proved positive effects of supplementation with oral
antioxidants such as vitamin C, vitamin E or carotene. Some recent studies showed that therapy
with antioxidants has no effect and can even increases
mortality (2333). The intake of only one antioxidant
could alter the complex system of endogenous antioxidative defence of cells or necrosis or apoptosis
pathways. It is wrong to search the redox magic bullet among different compounds with increased redox
potential. Better approach is to focus on detailed
understanding of the complex redox system of human
cells and to investigate the synergistic effects of different antioxidants on total oxidative stress. There are
other methods to decrease oxidative stress, e.g. prevention of free radical formation at first instance
(10). We have to realize that usage of synthetic vitamin supplements is not an alternative to regular consumption of fruits and vegetables. It is quite possible
that many antioxidants are still undiscovered; furthermore the combination of antioxidants in fruits
and vegetables cause their reciprocal regeneration
and consecutively intensifies their defense from free
radicals. However, deficiency of vitamins B-12, folic
acid, B-6, C or E, or iron or zinc appears to mimic
radiation damage of DNA by causing single- and
double-strand breaks, oxidative lesions or both. Evidence is accumulating that a multivitamin/mineral
supplement could improve the health of specific
populations, e.g. poor, young, obese, elderly and
people exposed to increased ROS from the environment, but the lack of sufficient double-blind, multicentric studies does not permit recommendations on
systemic usage of antioxidants. Nevertheless, antioxidant-rich diets with fruits and vegetables can be
recommended without any risk. It is important to
mention that antioxidants as dietary supplements
can protect in conditions of elevated oxidative stress
and that they could be therapeutically effective in
those individuals. On the other hand, presented evidences show that synthetic antioxidant supplements
cannot protect appropriately or entirely against oxidative stress in situations where it is not increased
and that their usage to prevent diseases or slow aging
is controversial.
Conclusions
A wide variety of antioxidants or other phytochemicals, such as licopene, coenzyme Q, glutathione, carnosine, selenium, zinc, bioflavonoids, green tea
polyphenols, grape seed proanthocyanidins, resveratrol, silymarin, genistein, and others have been
reported to possess substantial protective effects on
UV-induced skin inflammation, oxidative stress and
DNA damage.
In order to determine oxidative stress in individuals, both, the ROS potential as well as the antioxidative

112

B. Poljsak et al.

defense potential should be measured in blood or


cytosol. Numerous in vitro antioxidational potential
determinations exist that are easy to perform and
largely used in screening. It is important to recognize
oxidative imbalance in individuals early in order to
prevent the long term oxidative and antioxidative
stresses (12). These requirements should be considered when determining individuals oxidative status
before begining or ending the therapy with antioxidants. Even better approach would be to monitor in
vivo the oxidative stress in skin cells. Several techniques exist to assess oxidative stress in the skin and
many methods are currently under development, e.g.
electron spin resonance, fluorescence probes, cyclic
voltammetry, but they are not routinely used (10).
From the consumers point of view, they would be
interested in the information regarding antioxidative
potential of skin products.
There is no widely accepted and standardized
method to evaluate antioxidative capacity of skincare products, like SPF rating system in sunscreens.
ORAC (Oxygen Radical Absorbance Capacity) and
ABEL-RAC (Analysis By Emitted Light-Relative
Antioxidant Capacity) are both accepted worldwide
as a standard measure of the antioxidative capacity
of foods, and a similar rating system could be developed for the antioxidative capacity of skin-care products (34). Although many methods already exist for
evaluation of skin-care cosmetic antioxidative capacity, e.g. indirect spectorphotometric determination of
a free radical DPPH or ABTS (3436), they are not
commercially available for skin-care products found
on the market. The standardization and evaluation of
antioxidative potential of skin-care products could
help consumers to choose products with effective
antioxidative properties.
Disclosures of interest: Authors have no financial and
conflict of interests to disclose. The authors alone are
responsible for the content and writing of the paper.

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